Malarone

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Malarone

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Vomiting and Diarrhea

Absorption of atovaquone may be reduced in patients with
diarrhea or vomiting. If MALARONE is used in patients who are vomiting,
parasitemia should be closely monitored and the use of an antiemetic
considered. [See DOSAGE AND ADMINISTRATION] Vomiting occurred in up to
19% of pediatric patients given treatment doses of MALARONE. In the controlled
clinical trials, 15.3% of adults received an antiemetic when they received
atovaquone/proguanil and 98.3% of these patients were successfully treated. In
patients with severe or persistent diarrhea or vomiting, alternative
antimalarial therapy may be required.

Relapse of Infection

In the event of recrudescent P. falciparum infections
after treatment with MALARONE or failure of chemoprophylaxis with MALARONE,
patients should be treated with a different blood schizonticide.

Hepatotoxicity

Elevated liver laboratory tests and cases of hepatitis
and hepatic failure requiring liver transplantation have been reported with
prophylactic use of MALARONE.

Severe or Complicated Malaria

MALARONE has not been evaluated for the treatment of
cerebralmalaria or other severe manifestations of complicated malaria,
including hyperparasitemia, pulmonary edema, or renal failure. Patients with
severe malaria are not candidates for oral therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity studies have not been performed with
atovaquone in combination with proguanil. Effects of MALARONE on male and
female reproductive performance are unknown.

Atovaquone

A 24-month carcinogenicity study in CD rats was negative
for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54
times the average steady-state plasma concentrations in humans during
prophylaxis of malaria. In CD-1 mice, a 24-month study showed treatment-related
increases in incidence of hepatocellular adenoma and hepatocellular carcinoma
at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least
15 times the average steady-state plasma concentrations in humans during
prophylaxis of malaria.

Atovaquone was negative with or without metabolic
activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No
evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Atovaquone did not impair fertility in male and female
rats at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately
7.3 times the estimated human exposure during treatment of malaria based on
AUC.

Proguanil

No evidence of a carcinogenic effect was observed in
24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day
corresponding to 1.5 times the average human plasma exposure during prophylaxis
of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day
corresponding to 1.1 times the average human plasma exposure during prophylaxis
of malaria based on AUC.

Proguanil was negative with or without metabolic
activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma
mutagenesis assay. No evidence of genotoxicity was observed in the in vivo
Mouse Micronucleus assay.

Cycloguanil, the active metabolite of proguanil, was also
negative in the Ames test, but was positive in the Mouse Lymphoma assay and the
Mouse Micronucleus assay. These positive effects with cycloguanil, a
dihydrofolate reductase inhibitor, were significantly reduced or abolished with
folinic acid supplementation.

A fertility study in Sprague-Dawley rats revealed no
adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to
0.04-times the average human exposure during treatment of malaria based on
AUC). Fertility studies of proguanil in animals at exposures similar to or
greater than those observed in humans have not been conducted.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Atovaquone

Atovaquone was not teratogenic and did not cause
reproductive toxicity in rats at doses up to 1,000 mg/kg/day corresponding to
maternal plasma concentrations up to 7.3 times the estimated human exposure
during treatment of malaria based on AUC. In rabbits, atovaquone caused adverse
fetal effects and maternal toxicity at a dose of 1,200 mg/kg/day corresponding
to plasma concentrations that were approximately 1.3 times the estimated human
exposure during treatment of malaria based on AUC. Adverse fetal effects in rabbits,
including decreased fetal body lengths and increased early resorptions and
post-implantation losses, were observed only in the presence of maternal
toxicity.

In a pre- and post-natal study in rats, atovaquone did
not produce adverse effects in offspring at doses up to 1,000 mg/kg/day
corresponding to AUC exposures of approximately 7.3 times the estimated human
exposure during treatment of malaria.

Proguanil

A pre- and post-natal study in Sprague-Dawley rats
revealed no adverse effects at doses up to 16 mg/kg/day of proguanil
hydrochloride (up to 0.04-times the average human exposure based on AUC). Pre-
and post-natal studies of proguanil in animals at exposures similar to or
greater than those observed in humans have not been conducted.

Atovaquone and Proguanil

The combination of atovaquone and proguanil hydrochloride
was not teratogenic in pregnant rats at atovaquone:proguanil hydrochloride (50:20
mg/kg/day) corresponding to plasma concentrations up to 1.7 and 0.1 times,
respectively, the estimated human exposure during treatment of malaria based on
AUC. In pregnant rabbits, the combination of atovaquone and proguanil
hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at
atovaquone:proguanil hydrochloride (100:40 mg/kg/day) corresponding to plasma
concentrations of approximately 0.3 and 0.5 times, respectively, the estimated
human exposure during treatment of malaria based on AUC.

There are no adequate and well-controlled studies of
atovaquone and/or proguanil hydrochloride in pregnant women. MALARONE should be
used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.

Falciparum malaria carries a higher risk of morbidity and
mortality in pregnant women than in the general population. Maternal death and
fetal loss are both known complications of falciparum malaria in pregnancy. In
pregnant women who must travel to malaria-endemic areas, personal protection
against mosquito bites should always be employed in addition to antimalarials. [See
PATIENT INFORMATION.]

The proguanil component of MALARONE acts by inhibiting
the parasitic dihydrofolate reductase [see CLINICAL PHARMACOLOGY].
However, there are no clinical data indicating that folate supplementation
diminishes drug efficacy. For women of childbearing age receiving folate supplements
to prevent neural tube birth defects, such supplements may be continued while
taking MALARONE.

Nursing Mothers

It is not known whether atovaquone is excreted into human
milk. In a rat study, atovaquone concentrations in the milk were 30% of the
concurrent atovaquone concentrations in the maternal plasma.

Proguanil is excreted into human milk in small
quantities.

Caution should be exercised when MALARONE is administered
to a nursing woman.

Pediatric Use

Prophylaxis of Malaria

Safety and effectiveness have not been established in
pediatric patients who weigh less than 11 kg. The efficacy and safety of
MALARONE have been established for the prophylaxis of malaria in controlled
trials involving pediatric patients weighing 11 kg or more [see Clinical
Studies].

Treatment of Malaria

Safety and effectiveness have not been established in
pediatric patients who weigh less than 5 kg. The efficacy and safety of
MALARONE for the treatment of malaria have been established in controlled
trials involving pediatric patients weighing 5 kg or more [see Clinical
Studies].

Geriatric Use

Clinical trials of MALARONE did not include sufficient
numbers of subjects aged 65 years and older to determine whether they respond
differently from younger subjects. In general, dose selection for an elderly
patient should be cautious, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, the higher systemic exposure to
cycloguanil, and the greater frequency of concomitant disease or other drug
therapy. [See CLINICAL PHARMACOLOGY.]

Renal Impairment

Do not use MALARONE for malaria prophylaxis in patients
with severe renal impairment (creatinine clearance < 30 mL/min). Use with
caution for the treatment of malaria in patients with severe renal impairment,
only if the benefits of the 3-day treatment regimen outweigh the potential risks
associated with increased drug exposure. No dosage adjustments are needed in
patients with mild (creatinine clearance 50 to 80 mL/min) or moderate
(creatinine clearance 30 to 50 mL/min) renal impairment. [See CLINICAL
PHARMACOLOGY.]

Hepatic Impairment

No dosage adjustments are needed in patients with mild or
moderate hepatic impairment [see CLINICAL PHARMACOLOGY]. No trials have
been conducted in patients with severe hepatic impairment.

Last reviewed on RxList: 3/19/2013
This monograph has been modified to include the generic and brand name in many instances.